Inflammation plays a critical role in tumorigenesis and it is known that many cancers are associated with sites of chronic inflammation. For instance, colon carcinogenesis is associated with inflammatory bowel diseases (IBD), Helicobacter pylori infection is the cause of stomach cancer, and hepatitis C viral infection correlates with liver carcinoma. Opposing effects of TNF on cancer have been described: high dose of TNF (acute inflammation) has antineoplastic effects, such as direct cytotoxicity on certain types of cancer, while endogenous low-dose of TNF (chronic inflammation) promotes cancer development. As a potent inducer of NF-kB activation, the tumor promoting effect of TNF is believed to be through activating this transcription factor. The constitutive activation of NF-kB is associated with many autoimmune inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease as well as certain cancers such as leukemia and lymphomas, breast cancer, and gastrointestinal cancers. NF-kB promotes tumorigenesis both by enhancing cell proliferation and by induction of anti-apoptotic genes. Inhibition of NF-kB is a potential anti-cancer therapy. However, one of the caveats in inhibiting NF-kB systemically is that NF-kB is indispensable for both innate and adaptive immune responses. Tissue-specific knock-out models allow to study the effects of selective targeting of the NF-kB pathway on tumorigenesis without affecting NF-kB in the whole organism. Due to the tumor promoting effect of TNF, TNF antagonists have been suggested as potential cancer treatment agents. Alternatively, targeting various molecules involved in TNFR1 signaling pathway upstream of NF-kB is another possible therapeutic strategy against cancer-promoting inflammatory responses. Using TRADD-deficient mice, we have shown that TRADD plays an important role in mediating TNF signaling. In addition, TRADD is involved in TLR3 and TLR4 signaling as well. It is known that Toll-like receptors (TLRs) play an essential role in the development of innate and adaptive immune responses and that TLR signaling triggers inflammation through the activation of NF-kB and other transcription factors. Moreover, recent studies suggest that one of the mechanisms by which tumors evade immune attack is through expressing TLRs. TLR signaling promotes tumor cell proliferation and reduces apoptosis. It enhances tumor invasion by regulating metalloproteinases and integrins and induces the synthesis of pro-inflammatory cytokines. Since deletion of TRADD will affect several signaling pathways, including TNFR1 and TLR3/4, TRADD is a potential target for blocking tumor-promoting inflammatory responses. Therefore, we have started to investigate the importance of TRADD-mediated inflammatory responses in tumor development with tissue-specific TRADD deletion in the mouse models of skin tumorigenesis. Macrophages are chief participants in host inflammatory responses of the innate immune system. Deregulation of macrophage differentiation and function may lead to diseases including cancer Following antigen stimulation, immature monocytes emigrate from blood vessels into peripheral tissues where they differentiate into mature macrophages. Macrophages are considered classically activated (M1) when stimulated by interferon (IFN) or lipopolysaccharide (LPS) to release nitric oxide (NO), important for killing intracellular pathogens, and alternatively activated (M2) when stimulated by interleukin (IL)-4 or IL-13 (M2a) to produce IL-10, transforming growth factor (TGF) and arginase-1 (Arg1), important for killing extracellular parasites. M2 can be further subdivided to those induced by immune complexes (ICs) and LPS or IL-1 (M2b) or those induced by IL-10, TGF or glucocorticoids (GC) (M2c) (51). The molecular processes that occur during monocyte/macrophage differentiation and polarization, particularly in the differentiation of M2 type macrophage, are not completelyunderstood. In recent studies, people have found that microRNAs have emerged as an important component in the differentiation and function of cells involved in the immune responses. Several miRNAs, including miR-223, miR-155, miR-146, and miR-125b, have a role in the innate immune system. As RNA molecules 22 nucleotides in length that are processed from larger transcripts by Drosha and Dicer nucleases, miRNAs are incorporated along with core argonaute proteins into the RNA-induced silencing complex. Such a system is particularly suitable for controlling cell differentiation, in which the development of new cellular properties involves changes in large protein sets and in which multiple components of an important pathway or pathways can be efficiently modulated by the expression of a single miRNA or a set of miRNAs. The capability of macrophages to express distinct functional phenotypes is typically manifested in pathological conditions, including cancer. Tumor-associated macrophages (TAMs), which represent the major inflammatory component of the stroma of many tumors, are critical mediators of tumor initiation, progression and metastasis. In contrast with normal macrophages, TAMs exhibit pro-tumoral functions, including the growth, survival, invasion, and metastasis of tumor cells as well as angiogenesis and lymphangiogenesis in tumors. TAMs have been shown to display an alternative M2 like activation phenotype and play a detrimental pro-tumoral role. Blocking TAMs? functions has been shown to have great inhibitory effect on tumorigenesis. We also plan to study the regulation of monocyte/macrophage differentiation. Particularly, how tumor cells regulates macrophages to become tumor associated macrophages. Most recently, we found that tumor necrosis/necroptosis-induced inflammation is critical for tumorigenesis.